The long term objectives of this project are to understand the biology of drug resistant HIV and optimize use of sequential drug combinations to delay the domination of the virus population by resistant viruses, to favor selection of less replicative viruses and to avoid selection of viruses with enhnaced replication. To achieve these aims the author proposes to achieve the following: Aim # 1. Characterize the mechanisms for persistence of antiviral effects following selection of a resistant population during combination therapies in vivo. Isolates obtained during therapy will be studied to determine if MDR occurs and if either constraints on resistance or impaired replication are associated with antiviral responses. Aim #2 is to characterize replicative functions of RT inhibitors-resistant mutants. Effects of resistance mutantions in RT on polymerase processivity and nucleotide misincorporation frequency will be characterized in various genetic backgrounds in vivo. Aim #3. To characterize relative replication capacities of MDR selected by different regimens in vitro and to identify strategies that minimize replication or resistant viruses in vitro and in vivo. Thus, MDR viruses will be selected in vitro. Different combination regimens will be ranked according to the relative replication impairment and resistance of the selected mutants. Clinical trials will test the hypothesis that HIV replication can be slowed down the most with a regimen whose best mutant is most impaired in replication and/or most constraint from changes which should improve its selective advantage.